Sökning: WFRF:(Zierath JR)
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IRS-1 serine phosph...
IRS-1 serine phosphorylation and insulin resistance in skeletal muscle from pancreas transplant recipients
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Bouzakri, K (författare)
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- Karlsson, HKR (författare)
- Karolinska Institutet
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Vestergaard, H (författare)
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Madsbad, S (författare)
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Christiansen, E (författare)
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- Zierath, JR (författare)
- Karolinska Institutet
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(creator_code:org_t)
- American Diabetes Association, 2006
- 2006
- Engelska.
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 55:3, s. 785-791
- Relaterad länk:
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http://diabetes.diab...
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http://kipublication...
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https://doi.org/10.2...
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Abstract
Ämnesord
Stäng
- Insulin-dependent diabetic recipients of successful pancreas allografts achieve self-regulatory insulin secretion and discontinue exogenous insulin therapy; however, chronic hyperinsulinemia and impaired insulin sensitivity generally develop. To determine whether insulin resistance is accompanied by altered signal transduction, skeletal muscle biopsies were obtained from pancreas-kidney transplant recipients (n = 4), nondiabetic kidney transplant recipients (receiving the same immunosuppressive drugs; n = 5), and healthy subjects (n = 6) before and during a euglycemic-hyperinsulinemic clamp. Basal insulin receptor substrate (IRS)-1 Ser (312) and Ser (616) phosphorylation, IRS-1–associated phosphatidylinositol 3-kinase activity, and extracellular signal–regulated kinase (ERK)-1/2 phosphorylation were elevated in pancreas-kidney transplant recipients, coincident with fasting hyperinsulinemia. Basal IRS-1 Ser (312) and Ser (616) phosphorylation was also increased in nondiabetic kidney transplant recipients. Insulin increased phosphorylation of IRS-1 at Ser (312) but not Ser (616) in healthy subjects, with impairments noted in nondiabetic kidney and pancreas-kidney transplant recipients. Insulin action on ERK-1/2 and Akt phosphorylation was impaired in pancreas-kidney transplant recipients and was preserved in nondiabetic kidney transplant recipients. Importantly, insulin stimulation of the Akt substrate AS160 was impaired in nondiabetic kidney and pancreas-kidney transplant recipients. In conclusion, peripheral insulin resistance in pancreas-kidney transplant recipients may arise from a negative feedback regulation of the canonical insulin-signaling cascade from excessive serine phosphorylation of IRS-1, possibly as a consequence of immunosuppressive therapy and hyperinsulinemia.
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Diabetes
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